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724 The Journal of Rheumatology 2008; 35:4

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Prospective Study of the Association Between NAT2 GeneHaplotypes and Severe Adverse Events with SulfasalazineTherapy in Patients with Rheumatoid Arthritis

To the Editor:

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease char-acterized by chronic inflammation of synovial tissue, resulting in destruc-tion of multiple joints and eventually leading to severe disability. Treatmentof RA with disease modifying antirheumatic drugs can prevent jointdestruction1,2 and reduce mortality3, yet important adverse events are asso-ciated with the use of these agents. Tanaka, et al4 reported that the occur-rence of adverse events with sulfasalazine (SSZ) therapy might be depend-ent upon genetic variations of the N-acetyltransferase 2 (NAT2) gene.Recently, Taniguchi, et al5 conducted a retrospective replication study ofthe association between NAT2 polymorphisms and adverse events withSSZ therapy. We examined the association between NAT2 genotypes andsevere adverse events with SSZ therapy among patients with RA in aprospective study.

More than 5000 patients with RA have attended the outpatient clinic ofthe Institute of Rheumatology, Tokyo Women’s Medical University. Morethan 99% of those patients are Japanese. All patients with RA met the 1987American College of Rheumatology classification criteria6. Of these 5000patients, 20%–30% were treated with SSZ. Between May 2006 and April2007, 4 of the SSZ-treated patients, all Japanese, required hospitalizationfor severe adverse events and were admitted to Aoyama Hospital, TokyoWomen’s Medical University.

Our previous study of genotypes at 4 single-nucleotide polymorphism(SNP) sites in the NAT2 gene enabled us to infer the haplotypes and diplo-type configurations for the majority of Japanese individuals7. These 4 SNPyield 6 haplotypes in the NAT2 gene in the Japanese population: NAT2*4,NAT2*5B, NAT2*5E, NAT2*6A, NAT2*7B, and NAT2*13. NAT2*4 is thewild-type haplotype; the remaining haplotypes are mutant types. ATaqMan kit (Applied Biosystems, Foster City, CA, USA) was used todetermine genotypes at the 4 SNP sites by allelic discrimination chemistry.Genotypes were determined at the 4 SNP loci in the NAT2 gene. From thegenotyping data, we inferred the diplotype configuration for each individ-ual, using Penhaplo software8,9.

Table 1 shows clinical characteristics of the 4 patients who experiencedsevere adverse events with SSZ therapy (1 g daily). Fever, pancytopenia,and severe rash, including Stevens-Johnson syndrome, occurred. The inter-val between initiation of SSZ treatment and first observation of severeadverse events was 11.8 ± 6 days (mean ± standard deviation). Although 2of 4 cases were complicated with systemic lupus erythematosus, diseaseactivity was low and deteriorated no further after administration of SSZ.DNA samples from the 4 patients were collected with the approval of eth-ical committees of Tokyo Women’s Medical University. Genomic DNAanalysis revealed that all 4 patients lacked the NAT2*4 haplotype. Althoughwe did not investigate the background of the NAT2 gene in RA patients atour outpatient clinic in this study, 2 articles from our institution had alreadyindicated that the frequency of the diplotype configuration without theNAT2*4 haplotype was only 5.6%–7.5% in Japanese patients with RA4,5.

Adverse events resulting from SSZ seem to be rare among Caucasians.The discrepancy may be explained by the fact that the NAT2*5 haplotypeis common among Caucasians10 but not among Asians. It is likely that themajority of the Caucasians who lack the NAT2*4 haplotype possess at leastone NAT2*5 haplotype copy. NAT2*5 haplotype may code for a leakyenzyme, although further studies are required to prove this.

We found that all 4 patients who experienced severe adverse eventswhen treated with SSZ had the diplotype configuration without the NAT2*4haplotype. Our observations suggest that lack of the NAT2*4 haplotype isstrongly linked to adverse events with SSZ therapy in Japanese patientswith RA.

MAKOTO SOEJIMA, MD; YASUSHI KAWAGUCHI, MD; MASAKOHARA, MD; NAOYUKI KAMATANI, MD, Institute of Rheumatology,Tokyo Women’s Medical University, Tokyo, Japan. Address reprintrequests to Dr. Y. Kawaguchi, Institute of Rheumatology, Tokyo Women’sMedical University, 10-22 Kawada-cho, Shinjyuku-ku, Tokyo 162-0054,Japan. E-mail: [email protected]

Supported in part by a grant from the Ministry of Health, Labour, andWelfare of Japan.

REFERENCES1. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of

leflunomide compared with placebo and sulphasalazine in activerheumatoid arthritis: a double-blind, randomised, multicentre trial.European Leflunomide Study Group. Lancet 1999;353:259-66.

2. Ikari K, Momohara S. Images in clinical medicine. Bone changesin rheumatoid arthritis. N Engl J Med 2005;353:e13.

3. Krause D, Schleusser B, Herborn G, Rau R. Response tomethotrexate treatment is associated with reduced mortality inpatients with severe rheumatoid arthritis. Arthritis Rheum2000;43:14-21.

4. Tanaka E, Taniguchi A, Urano W, et al. Adverse effects ofsulfasalazine in patients with rheumatoid arthritis are associated

INSTRUCTIONS FOR LETTERS TO THE EDITOREditorial comment in the form of a Letter to the Editor is invited.The length of a letter should not exceed 800 words, with a maximumof 10 references and no more than 2 figures or tables; and no subdi-vision for an abstract, methods, or results. Letters should have nomore than 4 authors. Financial associations or other possible con-flicts of interest should be disclosed.Letters should be submitted via our online submission system, avail-able at the Manuscript Central website: http://mc.manuscriptcen-tral.com/jrheum For additional information, contact the ManagingEditor, The Journal of Rheumatology, E-mail: [email protected]

Table 1. Clinical characteristics of 4 patients with RA who experiencedsevere adverse events with sulfasalazine therapy.

Patient Sex/Age, Interval, Adverse Complication NAT2yrs days* Events Gene

Haplotype

1 F 31 4 Fever, rash SLE *5B/*7B2 M 70 16 Pancytopenia SLE *6A/*6A3 F 35 17 Pancytopenia — *6A/*134 F 28 10 Fever, SJS — *6A/*6A

* Interval between initiation of treatment and first observation of adverseevent(s). SJS: Stevens-Johnson syndrome; SLE: systemic lupus erythe-matosus.

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725Letters

with diplotype configuration at the N-acetyltransferase 2-gene.J Rheumatol 2002;29:2492-9.

5. Taniguchi A, Urano W, Tanaka E, et al. Validation of theassociations between single nucleotide polymorphisms orhaplotypes and responses to disease-modifying antirheumatic drugsin patients with rheumatoid arthritis: a proposal for prospectivepharmacogenomic study in clinical practice. PharmacogenetGenomics 2007;17:383-90.

6. Arnett FC, Edworthy SM, Bloch DA, et al. The AmericanRheumatism Association 1987 revised criteria for the classificationof rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.

7. Soejima M, Sugiura T, Kawaguchi Y, et al. Association of thediplotype configuration at the N-acetyltransferase 2 gene withadverse events with co-trimoxazole in Japanese patients withsystemic lupus erythematosus. Arthritis Res Ther 2007;9:R23.

8. Furihata S, Ito T, Kamatani N. Test of association betweenhaplotypes and phenotypes in case-control studies: examination ofvalidity of the application of an algorithm for samples from cohortor clinical trials to case-control samples using simulated and realdata. Genetics 2006;174:1505-16.

9. Ito T, Inoue E, Kamatani N. Association test algorithm between aqualitative phenotype and a haplotype or haplotype set usingsimultaneous estimation of haplotype frequencies, diplotypeconfigurations and diplotype-based penetrances. Genetics2004;168:2339-48.

10. Mahid SS, Colliver DW, Crawford NPS, et al. Characterization ofN-acetyltransferase 1 and 2 polymorphisms and haplotype analysisfor inflammatory bowel disease and sporadic colorectal carcinoma.BMC Medical Genetics 2007;8:28.

Progressive Multifocal Leukoencephalopathy in a MinimallyImmunosuppressed Patient with Systemic LupusErythematosus Treated with Dapsone

To the Editor:

Progressive multifocal leukoencephalopathy (PML) is a rare and often fataldemyelinating disease due to reactivation of a latent infection with thepapova-like polyomavirus JC (JCV)1,2. Although cases have been reportedin immunocompetent patients3, most patients are severely immunosup-pressed4. Interest in this infection in rheumatic disease has recentlyincreased due to the reports of PML occurring in 2 patients with systemiclupus erythematosus (SLE) treated with rituximab5. There have been 24cases reported of PML occurring in patients with SLE, and the topic ofPML in patients with rheumatic diseases has recently been reviewed6. Wedescribe an additional patient with SLE who developed PML while beingtreated with low-dose prednisone, hydroxychloroquine (HCQ), and dap-sone. To our knowledge, this is the first case of PML occurring in a patienttreated with dapsone.

The patient was a 62-year-old Caucasian woman with a 25-year histo-ry of SLE manifested in the past by pericarditis, recalcitrant cutaneousmanifestations, and anti-DNA antibodies and hypocomplementemia, with-out renal or central nervous system manifestations. She was treated withprednisone 60 mg daily at her presentation with pericarditis. She had norecurrences of pericarditis and subsequently has been treated with low-doseprednisone every other day, except for occasional increases to no more than20 mg daily for not longer than 3 weeks’ duration. She had been treatedwith HCQ for 15 years and had been taking 600 mg daily for the past 8months. Five years ago, she had received thalidomide for 8 weeks for treat-ment of antimalarial-resistant subacute cutaneous disease, but she hadnever been treated with azathioprine, cyclophosphamide, mycophenolatemofetil, rituximab, or other biologic agents. Three months prior to onset ofsymptoms of PML, dapsone 100 mg daily was added to her regimen of

prednisone 2.5 mg every other day and HCQ 600 mg daily. In April 2006,she experienced sudden onset of left arm and left side facial numbness, leftside apraxia and bradykinesia, and hesitancy in her speech. A brain mag-netic resonance image (MRI) showed a focal lesion in the white matter ofthe right parietal lobe that was hypointense on T1-weighted images andhyperintense on T2-weighted and FLAIR images, with surrounding edemaand an area of enhancement with gadolinium, measuring 3 × 1 cm. A biop-sy of the lesion revealed focal infarction, reactive changes, and histiocyto-sis. B and T cells were present in the perivascular areas. No neoplasm wasfound. HIV antibodies were negative. Cultures were negative for bacteria,fungi, and acid-fast bacilli, but she was treated empirically with van-comycin, metronidazole, and ceftriaxone. After discharge, JC virus infec-tion was documented on the basis of the histologic findings on brain-biop-sy tissue of large, round, dark nuclei with “ground-glass” appearance con-sistent with infected oligodendrocytes. These cells were immunohisto-chemically positive for papova virus and p53. Perivascular lymphocyticinfiltration and a background of macrophages were present. Her SLE wasfelt to be well controlled, dapsone was discontinued, and antibiotics werechanged to cidofovir. A repeat MRI 3 weeks after presentation showed pro-gression of the parietal lesion with enhancement measuring 4.5 × 2.5 cm.After 3 months of treatment, she developed severe bilateral uveitis, and cid-ofovir was discontinued. She was then given levetiracetam prophylactical-ly because of extensive brain damage evident on MRI. In July 2006, herMRI showed improvement, the area of enhancement decreasing in size to4 × 2.4 cm. By December 2006, the area of enhancement had all but dis-appeared (2 mm). Her most recent MRI, in July 2007, showed no area ofenhancement. Her SLE has remained quiescent to date and she is present-ly taking HCQ 400 mg daily and levetiracetam. Her neurological deficitshave improved steadily with both physical and speech therapy, althoughshe retains some residual left side apraxia. She has been able to return towork full-time.

PML is an often progressive and fatal demyelinating disease reportedto occur in both immunosuppressed and immunocompetent patients.Clinically, it is manifested by motor weakness, sensory deficits, limb andgait ataxia, visual loss, cognitive impairment and mental deficits, personal-ity changes, and dementia, correlating with lesions in the subcortical whitematter and cortical myelin7. Neuroimaging by brain MRI shows areas ofhypointensity or isointensity in the subcortical white matter on T1–weight-ed images that are hyperintense on T2-weighted and FLAIR imaging8-10.Typical lesions do not exhibit either mass effects or contrast enhancement.Occasionally, however, the lesions may show surrounding edema andenhancement with gadolinium. These unusual radiologic findings havebeen most often observed in AIDS patients treated with highly activeantiviral therapy, and may be associated with a more favorable outcomethan classic PML11. This inflammatory variant of PML has recently beenobserved in patients without HIV infection12. These more unusual radi-ographic findings were observed in our patient. While these findings areconsidered characteristic of so-called inflammatory PML, the diagnosis inour patient was established definitely by the pathological and immunohis-tochemical findings on brain biopsy, which are considered the gold stan-dard. Pathologically, the JC virus infects the nuclei of oligodendrocytes andastrocytes and such nuclei are large, round, and dark with a glassy or“ground-glass” appearance. The JCV-infected cells can be confirmed byimmunohistochemistry for polyomavirus proteins, as was the case with ourpatient, or in situ hybridization for JCV DNA on infected tissue13,14. As analternative to brain biopsy, the diagnosis of PML can be established bypolymerase chain reaction detection of JCV DNA in cerebrospinal fluid(CSF)15.

With this additional patient, there are now 25 patients with SLE whohave developed PML reported in the literature. This patient had not beentreated with immunosuppressive medications for several years prior to theonset of her JCV infection, was not immunosuppressed at the time of JCVinfection, and was HIV negative. A unique feature is that this appears to bethe first reported patient to develop PML while taking dapsone. Dapsone isan antiparasitic agent most often used to treat leprosy, Pneumocystis






carinii, and dermatitis herpetiformis. It is useful in treating cutaneous vas-culitis and cutaneous lupus16,17. Dapsone has minimal effects on T and Bcell mitogenesis18, and its mechanism of action appears to be related to itseffects on neutrophil function and adherence19-21. Its use in SLE is basedon its utility in other cutaneous diseases and favorable clinical responses inpatients with cutaneous lupus, although its specific mechanism of action insystemic lupus has not been elucidated. PML has been reported to occur inpatients treated with natalizumab, an antagonist of α4 integrin, a biologicagent used in patients with multiple sclerosis and Crohn’s disease, withplanned uses in rheumatoid arthritis22,23. It has been hypothesized thatnatalizumab may promote the development of PML, at least partially by itsblockade of trafficking of hematologic cells into the CSF24,25. It is possiblethat dapsone, by its inhibition of neutrophil function and adherence, couldin a similar manner disrupt inflammatory cell trafficking into the CSF.However, until further cases of PML occur in patients taking dapsone, thepresent case must be considered a coincidental occurrence.

Several years before the onset of JCV infection, the patient was treatedwith thalidomide. Thalidomide is a known inhibitor of proinflammatoryTh1 cytokines, most notably tumor necrosis factor-α26. However, she hadnot taken this medication in many years and it is unlikely that it had anylongterm effects on her level of immunocompetency. Aside from the use ofdapsone, she was not receiving immunosuppressive agents in the conven-tional sense. She therefore is the tenth of the reported 25 SLE patients withPML to be relatively immunocompetent at the time of JCV infection. Thissuggests that factors other than iatrogenic immunosuppression, includingSLE itself, may be contributing to susceptibility to JCV infection in thesepatients.

Despite the short duration of treatment with cidofovir, limited by thedevelopment of drug-induced uveitis27, this patient has improved steadily.As noted in the literature, gadolinium enhancement of the parietal lesion onMRI scanning, consistent with inflammatory PML, and its subsequent res-olution coinciding with her clinical improvement, may have favorableprognostic significance11,12. It is possible that the relative immunocompe-tency of this patient contributed to her positive outcome.

In summary, this is a case of a minimally immunosuppressed patientwith SLE who developed PML while taking dapsone, a medication not pre-viously associated with development of PML. Although dapsone haseffects on leukocyte trafficking that could affect susceptibility to JCVinfection, this association must be considered coincidental until furthercases are reported. While profound immunosuppression is the usual back-ground in non-lupus patients with PML, 40% of the reported patients withSLE have been relatively immunocompetent at the time of JCV infection.Our patient’s relative immunocompetence may have contributed to her pos-itive outcome.

NEIL I. STAHL, MD, FACP, FACR, Clinical Associate Professor of Medicine,Georgetown University School of Medicine, Arthritis and RheumaticDisease Associates, 6035 Burke Centre Pkwy, Suite 280, Burke, Virginia22015, USA.

Address reprint requests to Dr. Stahl. The author thanks Phillip C. Fox,DDS, for his critical reading of the manuscript.

REFERENCES1. Padgett BL, Walker DL, ZuRhein GM, Eckroede RJ, Dessel BH.

Cultivation of papova-like virus from human brain with progressivemultifocal leukoencephalopathy. Lancet 1971;1:1257-60.

2. Weiner LP, Herndon RM, Narayan O, et al. Isolation of virus relatedto SV40 from patients with progressive multifocalleukoencephalopathy. N Engl J Med 1972;286:385-90.

3. Rockwell D, Ruben FL, Winkelstein A, Mendelow H. Absence ofimmune deficiencies in a case of progressive multifocalleukoencephalopathy. Am J Med 1976;61:433-6.

4. Eng PM, Turnbull BR, Cook SF, Davidson JE, Kurth T, Seeger JD.Characteristics and antecedents of progressive multifocal

leukoencephalopathy in an insured population. Neurology2006;67:884-6.

5. US Food and Drug Administration. FDA alert: rituximab (marketedas Rituxan). December 2006. Internet. Available from:www.fda.gov/cder/drug/InfoSheets/HCP/rituximab.pdf. AccessedJanuary 8, 2008.

6. Calabrese LH, Molloy ES, Huang D, Ransohoff RH. Progressivemultifocal leukoencephalopathy in rheumatic diseases: evolvingclinical and pathologic patterns of disease. Arthritis Rheum2007;56:2116-28.

7. Brooks BR, Walker DL. Progressive multifocalleukoencephalopathy. Neurol Clin 1984;2:299-313.

8. Whiteman ML, Post MJ, Berger LG, Tate LG, Bell MD, LimonteLP. Progressive multifocal leukoencephalopathy in 47 HIV-positivepatients: neuroimaging with clinical and pathologic correlation.Radiology 1993;187:233-40.

9. Da Pozzo S, Manara R, Tonello S, Carollo C. Conventional anddiffusion-weighted MRI in progressive multifocalleukoencephalopathy: new elements for identification and followup.Radiol Med Torino 2006;111:971-7.

10. Kuker W, Mader I, Nagele T, et al. Progressive multifocalleukoencephalopathy: value of diffusion-weighted and contrast-enhanced magnetic resonance imaging for diagnosis and treatmentcontrol. Eur J Neurol 2006;13:819-26.

11. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressivemultifocal leukoencephalopathy: harmful or beneficial?J Neurovirol 2003;9 Suppl 1:25-31.

12. Huang D, Cossoy M, Li M, et al. Inflammatory progressivemultifocal leukoencephalopathy in human immunodeficiency virus-negative patients. Ann Neurol 2007;62:34-9.

13. von Einsiedel RW, Fife TD, Aksamit AJ, et al. Progressivemultifocal leukoencephalopathy in AIDS: a clinicopathologic studyand review of the literature. J Neurol 1993;240:391-406.

14. Procop GW, Beck RC, Pettay JD, et al. JC virus chromogenic insitu hybridization in brain biopsies from patients with and withoutPML. Diagn Mol Pathol 2006;15:70-3.

15. Bossolasco S, Calori G, Moretti F, et al. Prognostic significance ofJC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin InfectDis 2005;40:738-44.

16. Carlson JA, Cavaliere LF, Grat-Kels JM. Cutaneous vasculitis: diag-nosis and management. Clin Dermatol 2006;24:414-29.

17. Sontheimer RD. Subacute cutaneous lupus: 25-year evolution of aprototypic subset (subphenotype) of lupus erythematosus defined bycharacteristic cutaneous, pathological, immunological, and geneticfindings. Autoimmun Rev 2005;4:253-63.

18. Kelso JM, Bai CL, Ahokas JT, Wright PF. In vitro effects of MOCAand dapsone on rat hepatic and splenic immune cells.Immunopharmacology 1997;35:183-93.

19. Coleman MD. Dapsone: modes of action, toxicity and possiblestrategies for increasing patient tolerance. Br J Dermatol1993;129:507-13.

20. Debol SM, Herron MJ, Nelson RD. Anti-inflammatory action ofdapsone: inhibition of neutrophil adherence is associated withinhibition of chemoattractant-induced signal transduction. J LeukocBiol 1997;62:827-36.

21. Suda T, Suzuki Y, Matsui T, et al. Dapsone suppresses humanneutrophil superoxide production and elastase release in a calcium-dependent manner. Br J Dermatol 2005;152:887-95.

22. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plusinterferon ß-1a for relapsing multiple sclerosis. N Engl J Med2006;354:911-23.

23. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocalleukoencephalopathy after natalizumab therapy for Crohn’s disease.N Engl J Med 2005;353:362-8.



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24. Von Andrian UH, Engelhardt B. α4 integrins as therapeutic targetsin autoimmune disease [editorial]. N Engl J Med 2003;348:68-72.

25. Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8:1275.26. Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol

2007;39:1489-99.27. Tacconelli E, Tumbarello M, Rabagliati R, et al. Correlation

between cidofovir-associated uveitis and failing immunorestorationduring HAART. Eur J Microbiol Infect Dis 2003;22:114-7.

Pseudotumoral Presentation of Calcium PyrophosphateDihydrate Crystal Deposition Disease

To the Editor:

Chondrocalcinosis is a microcrystalline disease characterized radiographi-cally by multiple foci of calcification in hyaline and fibrocartilage of thejoints and intervertebral discs. Initially described by Zitnan and Sit’aj1, ithas recently been more appropriately designated calcium pyrophosphatedihydrate (CPPD) crystal deposition disease. This term also encompassesthe tumorous form of the disease, designated tophaceous pseudogout.

We describe 2 cases of tophaceous pseudogout presenting as a singlecalcified soft-tissue mass with no evidence of CPPD crystal deposition dis-ease in any other joint.

Case 1. A 76-year-old woman presented with a history of swelling andincreasing pain of the right popliteal fossa leading to inability to bend theknee. In her history, she mentioned asthma in childhood and a Colles frac-ture 2 years before presentation. On examination, the overlying skin wasnormal. Palpation revealed a soft-tissue mass in the popliteal fossa associ-ated with moderate pain. Laboratory findings were normal; in particularthere was no inflammatory syndrome. Conventional radiographs and mul-tidetector computed tomography (MDCT) showed a 3-cm nodular mass inthe popliteal fossa, with multiple central or peripheral, arciform and annu-lar calcific deposits suggesting a cartilaginous matrix. The mass wasresponsible for a large erosion of the adjacent bone, i.e., the posterior cor-tex of the femoral metaphysis. Considering the cartilaginous characteristicsof the tumoral matrix and the presence of pain, which could not beexplained by any associated intraarticular disorder, the diagnosis of subpe-riosteal chondrosarcoma was suspected and a surgical ablation of the tumorwas performed.

Histopathologic analysis showed deposits of CPPD crystals borderedby a fibrous connective tissue presenting a lobulated pattern with areas ofchondroid metaplasia. The crystals were short, rod-like to rhomboid, andbirefringent under polarized light. A diagnosis of tumorous calcific collec-tion with CPPD crystal deposition was made, also designated tophaceouspseudogout (Figure 1). Conventional joints including wrists, knees, andpubic symphysis were radiographied after the diagnosis to look for typicalsigns of intraarticular CPPD disease. Radiographs showed no calcificdeposits on the hyaline or fibrocartilage.

Case 2. A 41-year-old woman complained of gradually increasing pain ofthe hip for several years. She reported a major ski accident in the past (6years previously) with a large hematoma of the anterior proximal portionof the thigh. She had no relevant medical or surgical history. Conventionalradiographs, ultrasound, and high resolution MDCT showed a widely cal-cified and well circumscribed 4-cm mass of the iliopsoas tendon. The char-acteristics were those of a benign highly calcified lesion resembling atumoral calcinosis. On magnetic resonance imaging (MRI), the lesionshowed low signal intensity on T1-weighted images and high signal inten-sity on T2-weighted sequences with gadolinium enhancement. These MRIpatterns are also those of the cartilaginous lesions. Because of recurrentpain and a slow increase of the size of the lesion, surgical ablation wasperformed.

Histopathologic and microscopic examination showed a calcified

tumor with a fibrous stroma and broad areas of crystalline deposits associ-ated with focal spots of chondroid metaplasia and giant cells. The crystalswere rhomboid and birefringent under a polarized light. The diagnosis pro-posed was CPPD crystal deposition disease. Typically involved joints werescreened to look for articular CPPD deposition.

Three years later, a soft-tissue mass developed in the hip again, withfeatures similar to the previous episode. Needle biopsies and steroid infil-tration were performed under MDCT control. Microscopic examinationfound similar patterns to those of 3 years before, and the diagnosis ofpyrophosphate tophus recurrence was confirmed (Figures 2 and 3). Shereturned 6 months later with increasing pain of the same thigh and thenunderwent surgery. Complete ablation of the tumor was performed and thediagnosis of pyrophosphate tophus recurrence was confirmed.

CPPD disease is characterized by the presence of crystal deposits in hya-line and fibrocartilage of the joints. CPPD crystal deposition disease is gener-ally observed in middle-aged and elderly patients. Initial descriptions empha-sized the occurrence of “pseudogout” attacks, but further investigationsrevealed multiple additional clinical patterns. These patterns emphasize thecapacity of the disease to mimic a variety of other conditions including gout,rheumatoid arthritis, degenerative joint disease, neuropathic osteoarthropathy,and a rare condition described here, tophaceous pseudogout.

Soft-tissue calcified mass (tophaceous pseudogout) is a rare presenta-tion of CPPD disease, as described2-9. Some reports3-6 describe highly cal-cified masses that are difficult to differentiate from tumoral calcinosis.Some others emphasized radiological similarities with benign or malignantcartilaginous lesions.

Our cases support these various data, as initial diagnosis was tumoralcalcinosis in one case and subperiosteal chondrosarcoma in the other.Differentiation between the latter condition and pseudogout is difficultbecause of the presence of arciform and annular calcifications within thesoft-tissue mass. Diagnosis can be made even more difficult by histologi-cal data that can show areas of chondroid metaplasia, sometimes associat-ed with cellular atypia, simulating once again a cartilaginous lesion4,10.Surgical ablation is therefore necessary to identify the CPPD crystals in themass, in order to avoid misdiagnosis of benign or malignant cartilaginouslesion. In both our cases, metaplastic areas of cartilage were seen, but withno cellular atypia. In most reports, the soft-tissue masses were associatedwith calcifications within hyaline or fibrocartilage, making the diagnosisrelatively easy. Lambrecht, et al10 reported the case of a well circumscribedmass of amorphous calcification located in the soft tissue adjacent to thelesser trochanter. In that case, calcific deposits were present in the symphy-sis pubis and the femoral head. In another case5 the tophaceous pseudogoutof the sternoclavicular joint was also associated with severe pluriarticularchondrocalcinosis. Maugars, et al11 reported large periarticular calcifica-tions of the hips and pubis in a woman with diffuse primary chondrocalci-nosis, symptomatic in the knees. Serial articular and periarticular biopsies


Figure 1. Case 1. Sagittal CT section shows well defined soft-tissue masswith arciform and annular calcification.





showed CPPD in cartilage, synovia, capsula, tendon, and muscle. In con-trast, in both our cases, no calcific deposits were found in other joints, mak-ing the diagnosis almost impossible as long as the typical radiological pat-terns were not present. This specific pattern makes us question the mostappropriate term to designate this disease.

Based on literature data, the locations most commonly involved withtophaceous pseudogout are the wrist and digits2,3,9, the infratemporal fossa,and the temporomandibular joint4,7,8,12. However, many other locations canbe involved, such as the para-ischial region10, the base of the neck, cervi-cal spine6,13, sternoclavicular joint5, and mitral valve14.

To our knowledge, our report is the first to describe CPPD diseaseinvolving the iliopsoas tendon. Lambrecht, et al10 described tophaceouspseudogout adjacent to the lesser trochanter, but the lesion was intimately

associated with the semimembranous tendon. Sissons, et al9 also reportedthe presence of a highly cellular lesion adjacent to the right hip. The masswas located in the tissues adjacent to the bone and contained deposits ofCPPD crystals.

Surgical ablation of these lesions is the rule, mainly because this diag-nosis is usually not established and histopathologic confirmation is need-ed. Complete ablation is required, because the lesion is at risk of recurrenceafter partial and sometimes even complete ablation15,16. We observed arecurrence in one of our cases, after complete excision of the mass locatedin the iliopsoas myotendinous junction. Three years after surgery, a 3.5-cmmass reappeared at exactly the same location.

Because of its unusual presentation, location, and histology, tumoralCPPD crystal deposition presenting as a single soft-tissue calcified tumormay be misinterpreted as a soft-tissue cartilaginous lesion or tumoral cal-cinosis. It is necessary to identify the CPPD crystal components on biopsyfragments to avoid misdiagnosis.

SEBASTIEN BRUNOT, MD; Unité d’Imagerie Ostéo-articulaire, HôpitalPellegrin, CHU de Bordeaux; THIERRY FABRE, MD, Unité de ChirurgieOrthopédique, CHU Bordeaux; SEBASTIEN LEPREUX, MD, Serviced’Anatomo-Pathologie, Université Victor Segalen, Bordeaux; FRANCOISDIARD, MD, Unité d’Imagerie Ostéo-articulaire, Hôpital Pellegrin, CHUde Bordeaux; RICHARD MASSONNAT, MD, Service De Rhumatologie,Université Victor Segalen; NATHANAEL SABBAH, BA; OLIVIERHAUGER, MD, Unité d’Imagerie Ostéo-articulaire, Hôpital Pellegrin,CHU de Bordeaux.

Address reprint requests to Dr. S. Brunot, Université Victor SegalenBordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France.E-mail: [email protected]

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Clinical and radiological study. Ann Rheum Dis 1963;22:142-52.2. Ling D, Murphy W, Kyriakos M. Tophaceous pseudogout. AJR Am

J Roentgenol 1982;138:162-5.3. Yamakawa K, Iwasaki H, Ohjimi Y, et al. Tumoral calcium

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Figure 2. Case 2. MDCT axial native section shows a widely calcified massin the psoas tendon. There is no intraarticular disorder.

Figure 3. Case 2. Sagittal T2 fat-suppressed MR image taken simultane-ously with that in Figure 2. There is edema within and adjacent to thelesion (+) involving the psoas muscle (arrow). The femoral head remainsnormal (*).



729Corrections

report of a case. Pathol Int 1997;47:578-80.13. Biankin S, Jaworski R, Mawad S. Tumoural calcium pyrophosphate

dihydrate crystal deposition disease presenting clinically as amalignant soft tissue mass diagnosed on fine needle aspirationbiopsy. Pathology 2002;34:336-8.

14. Moon MR, Fann JI, Deedwania PC, Ferguson R, Kosek JC, BurdonTA. Tophaceous pseudogout of the mitral valve. Ann Thorac Surg1998;66:952-4.

15. Ishikawa K, Higashi I, Shimomura Y, Yonemura K. Deposition ofcalcium pyrophosphate dihydrate crystals in the hand. J Hand SurgAm 1988;13:943-8.

16. Dijkgraaf LC, De Bont LG, Liem RS. Calcium pyrophosphatedihydrate crystal deposition disease of the temporomandibularjoint: report of a case. J Oral Maxillofac Surg 1992;50:1003-9.

CorrectionsSong I-H, Appel H, Haibel H, et al. New onset of Crohn’sdisease during treatment of active ankylosing spondylitiswith etanercept. J Rheumatol 2008;3:532-6.

In the note “Added in Proof” to this report, the number“10” represents reference 10, and should appear in super-script, as follows. We regret the error.

“Added in Proof. During preparation of this manuscript, afourth case of new onset of Crohn’s disease during etaner-cept therapy was observed in our department; a 34-year-oldmale patient with AS who also participated in the clinicaltrial10 developed new onset of CD 66 months after initiationof etanercept.”

Qazi U, Lam C, Karumanchi SA, Petri M. Soluble Fms-liketyrosine kinase associated with preeclampsia in pregnancyin systemic lupus erythematosus. J Rheumatol 2008;35:631-4. A disclosure statement should have been pub-lished with this report, as follows: Dr. Karumanchi is a co-inventor on multiple patents filed by Beth Israel DeaconessMedical Center for the diagnosis and therapy of preeclamp-sia. He is a consultant to Beckman Coulter, AbbottDiagnostics, and Johnson & Johnson. We regret the error.




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